Growing evidence indicates that tumor development and progression of experimental skin squamous cell carcinoma (SCC) induced by chemical carcinogens and promoters, are a consequence of genetic lesions that include not only abnormalities in known oncogenes and tumor suppressor genes but also the overexpression of cell cycle related genes (CCRG) such as cyclin D1. In the present proposal, we intend to study a group of human SCC's of the oral cavity that have a strong etiological linkage with alcohol and tobacco consumption and also harbor similar abnormalities in cyclin D1. The principal objective of this proposal is to demonstrate alterations in CCRGs expression that contribute to tumor development and progression and investigate the mechanism underlying the increased level of CCRG protein expression. The hypothesis to be tested in this application is that increased expression of multiple G1 cyclins and their respective Cdk's can be used as markers of poor prognosis in human head and neck SCC's, and that this occurs in most cases without gene amplification mechanisms such as increased half-life of the protein. In order to achieve this we plan to: a) detect changes in G1/S cyclins, and their respective cyclin dependent kinases in oral cancer and its precursors, b) utilize an extensive epidemiological data bank at our disposal to evaluate the role of CCRG abnormalities in oral cancer as function of tobacco-alcohol consumption as well as dietary habits and family-clinical history, c) confirm in a large series of human lesions that CCRG overexpression could be used as marker of tumor progression and poor prognosis, d) determine which component of the invasive/metastatic cascade is implicated in this process of tumor progression and e) investigate in selected SCC cell lines systems which CCRGs are the most significant in inducing enhancement of the malignant phenotype, and which are the basic mechanisms behind the overexpression of CCRGs in SCC cells.